Foretinib (GSK1363089)

Foretinib (GSK1363089) is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met and KDR with IC50 of 0.4 nM and 0.9 nM. Less potent against Ron, Flt-1/3/4, Kit, PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.

c-MET/RON inhibitors restore sensitivity to lapatinib in SK-BR-3-LR cells. Cell growth was determined using the sulforhodamine B assay. The concentration used was 0.1 uM for crizotinib, MGCD-265, XL880, sunitinib, dasatinib, and TAE-684I. The phosphorylation of HER2, AKT and ERK1/2 was determined by Western blotting.

Research Area

Inhibition Profile

Foretinib (GSK1363089) is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met and KDR with IC50 of 0.4 nM and 0.9 nM. Less potent against Ron, Flt-1/3/4, Kit, PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.

Foretinib (GSK1363089) Mechanism

c-Met is an α–β heterodimer with an extracellular α-chain disulfide linked to the membrane-spanning chain harboring the intracellular tyrosine kinase domain. The β-chain consists of the remainder of the Met ectodomain, the transmembrane helix and the cytoplasmic portion. The cytoplasmic portion contains the juxtamembrane domain, kinase domain and a C-terminal tail. [1] C-terminal region is essential for downstream signalling and contains two crucial tyrosines (Tyr1349 and Tyr1356). On activation, Tyr1349 and Tyr1356 become autophosphorylated and serve as docking sites for a wide spectrum of transducers and adaptors. [2]
The crystal structure shows that Foretinib binds to c-Met by occupying the ATP-binding site and the adjacent pocket. Foretinib forms one hydrogen bond with the backbone amide of Met1160 in the kinase linker, and three other hydrogen bonds are formed between the malonamide and Met atoms external to the ATP binding pocket. The phenyl malonamide of Foretinib dislodges the phenylalanine of the DFG motif (Phe1223) from its activated conformation (“Phe-in”) binding pocket under the C-helix. Furthermore, Phe1223 forms a stabilized stacking interaction with the central fluorophenyl ring of Foretinib. This interaction leads to a pseudo-inactivated conformation where the catalytic machinery has been disrupted (“Phe-out”). The reorganization of the activation loop entirely buries the ligand, sequestering it from solvent and greatly enhancing the binding affinity. [3]
References
[1] Birchmeier C, et al. Nat Rev Mol Cell Biol. 2003, (12), 915-925.
[2] Schiering N, et al. Proc Natl Acad Sci U S A. 2003, 100(22), 12654-12659.
[3] Qian F, et al. Cancer Res. 2009, 69(20), 8009-8016.

Dr. Antonino Maria Sparta demonstrates a breakthrough in leukemia research by utilizing two inhibitors produced by Selleck Chemicals.

Product Description

Biological Activity

Description

Foretinib (GSK1363089) is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met and KDR with IC50 of 0.4 nM and 0.9 nM. Less potent against Ron, Flt-1/3/4, Kit, PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.

A single 100 mg/kg oral gavage dose of XL880 results in substantial inhibition of phosphorylation of B16F10 tumor Met and ligand (e.g., HGFor VEGF)-induced receptor phosphorylation of Met in liver and Flk-1/KDR in lung, which both persisted through 24 hours. Treatment with XL880 (30-100 mg/kg, once daily, oral gavage) results in reduction in tumor burden. The lung surface tumor burden is reduced by 50% and 58% following treatment with 30 and 100 mg/kg XL880, respectively. XL880 treatment of mice bearing B16F10 solid tumors also results in dose-dependent tumor growth inhibition of 64% and 87% at 30 and 100 mg/kg, respectively. For both studies, administration of XL880 is well tolerated with no significant body weight loss. [1] XL880 is developed to target abnormal signaling of HGF through Met and simultaneously target several receptors tyrosine kinase involved in tumor angiogenesis. XL880 caused tumor hemorrhage and necrosis in human xenografts within 2 to 4 hours, and maximal tumornecrosis is observed at 96 hours (after five daily doses), resulting in complete regression. [3]

Cell Assay:

B16F10, A549, and HT29 cells (1.2× 103 per well) are mixed with soft agar and seeded in a 96-well plate containing 10% FBS and EXEL-2880 over a base agar layer. For normoxic conditions, the plates are incubated (37°C) for 12 to 14 days in 21% oxygen, 5% CO2, and 74% nitrogen, whereas incubation (37 °C) under hypoxic conditions is done in a hypoxia chamber in 1% oxygen, 5% CO2, and 94% nitrogen. The number of colonies is evaluated under each condition following addition of 50% Alamar Blue and fluorescence detection.

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species

Baboon

Dog

Monkey

Rabbit

Guinea pig

Rat

Hamster

Mouse

Weight (kg)

12

10

3

1.8

0.4

0.15

0.08

0.02

Body Surface Area (m2)

0.6

0.5

0.24

0.15

0.05

0.025

0.02

0.007

Km factor

20

20

12

12

8

6

5

3

Animal A (mg/kg) = Animal B (mg/kg) multiplied by

Animal B Km

Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

* <1 mg/ml means slightly soluble or insoluble.* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Research Area

Customer Product Validation (2)

c-MET/RON inhibitors restore sensitivity to lapatinib in SK-BR-3-LR cells. Cell growth was determined using the sulforhodamine B assay. The concentration used was 0.1 uM for crizotinib, MGCD-265, XL880, sunitinib, dasatinib, and TAE-684I. The phosphorylation of HER2, AKT and ERK1/2 was determined by Western blotting.

Consistent with the cell proliferation data, the Western blot results demonstrated that only XL880, crizotinib, and MGCD-265 significantly inhibited AKT and ERK1/2 phosphorylation in SK-BR-3-LR cells when combined with lapatinib.

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Tech Support & FAQs

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

BMS-777607 is a Met-related inhibitor for c-Met, Axl, Ron and Tyro3 with IC50 of 3.9 nM, 1.1 nM, 1.8 nM and 4.3 nM, 40-fold more selective for Met-related targets versus Lck, VEGFR-2, and TrkA/B, and more than 500-fold greater selectivity versus all other receptor and non receptor kinases. Phase 1/2.